Plasma next-generation sequencing (NGS) in advanced non-small cell lung cancer (aNSCLC) patients (pts) treated with immune checkpoint inhibitors (ICIs): Impact of STK11 and TP53 mutations on outcome.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3046-3046
Author(s):  
Alberto Pavan ◽  
Elisabetta Zulato ◽  
Lorenzo Calvetti ◽  
Alessandra Ferro ◽  
Giorgia Nardo ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Genetic Alterations ◽  
Predictive Markers ◽  
Control Group ◽  
Tp53 Mutations ◽  
Multiple Tumor ◽  
Promising Tool ◽  
Next Generation Sequencing Ngs ◽  
The Impact ◽  
Generation Sequencing

3046 Background: ICIs revolutionized aNSCLC treatment. The next challenge lays on the search for predictive markers. Detection of multiple tumor-related genetic alterations through NGS in cell free DNA is a promising tool, provided the limited availability of tumor tissue in most cases. Methods: Between January 2017 and October 2019, aNSCLC pts consecutively referring to our Institution were prospectively screened with plasma NGS while included in two clinical trials: VISION (NCT02864992) and MAGIC trial, an observational study. In VISION trial NGS was performed in plasma (Guardant360 test) and tissue (Oncomine Focus Assay). In MAGIC Myriapod NGS-IL 56G Assay was used. Aim of the study was to evaluate the impact of STK11, KRAS and TP53 mutations (muts) on outcome of ICI-treated pts, with overall survival (OS) as primary endpoint. A control group of pts not receiving ICIs was also analyzed. Results: A total of 235 NSCLC pts were enrolled and received ICIs. 93 pts were analyzed in plasma at the time of beginning ICIs: median OS was 18.9 m (95% CI: 13.7-24.1) and median immune-related progression free disease (irPFS) 3.8 m (95% CI: 2.5-5.1). 49 (52.7%), 22 (23.7%) and 8 (8.6%) pts carried TP53, KRAS and STK11 pathogenic alterations, respectively. STK11 mutated pts showed a trend for worse OS compared with wildtype counterpart (14.9 m, 95% CI: 6.5-23.3, versus 20.3, 95% CI: 13.4-27.2, p = 0.192) KRAS muts had no impact on outcome. Pts with TP53 or STK11/KRAS co-mut (n = 3) had worse OS (12.3 m, 95% CI: 9.2-15.4; HR = 3, 95% CI: 1.6-5.8, p = 0.001 and 5.9 m, 95% CI: 1.4-7.6; HR = 2.9, 95% CI: 1.4-6.3, p = 0.007) and worse irPFS (2.8 m, 95% CI: 1.7-3.9, HR = 1.8 95% CI: 1.1-3.1, p = 0.03 and 1.2 m, 95% CI: 0.9-1.5, HR = 2.2 95% CI: 1.2-4.1, p = 0.01). Number of muts negatively impacts pts’ OS (HR = 1.2, 95% CI: 1.1-1.3, p = 0.02) and was higher among TP53 mutated pts (p < 0.001, Mann-Whitney test). In multivariate analysis, TP53 and STK11/KRAS retained significance. A control group of pts not receiving ICIs was analyzed (n = 101): median OS was 16.8 m (95% CI: 13-20.6). Nor STK11 (n = 10), nor STK11/KRAS (n = 6) had impact on OS (HR = 1.8, 95% CI: 0.7-4.7, p = 0.267 and 1.4, 95% CI: 0.7-3.0, p = 0.293) while the presence of TP53 muts (n = 41) was associated with shorter OS (11.4 m, 95% CI: 7.3-15.5; HR = 2.2, 95% CI: 1.2-4.2, p = 0.009). Conclusions: NGS performed in plasma might be used to detect predictive markers. TP53 muts in plasma at baseline had prognostic value, while STK11/KRAS muts were associated with worse outcome to ICIs.

scholarly journals Use of Biomarkers in Individualization of Treatment

2020 ◽  
Vol 18 (7.5) ◽  
pp. 989-991
Author(s):  
Jennifer J.D. Morrissette
Keyword(s):  
Massively Parallel Sequencing ◽  
Checkpoint Inhibitors ◽  
Genetic Alterations ◽  
Massively Parallel ◽  
Disease Course ◽  
Patients With Cancer ◽  
Appropriate Treatment ◽  
Clinical Trial Enrollment ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Next-generation sequencing (NGS), also known as massively parallel sequencing (MPS), offers broad detection of genetic alterations that, in approximately one-third of patients with cancer, are “actionable,” meaning that they can be targeted by available therapeutics or the detection of the alteration can lead to a change in therapy. NGS is useful in the diagnosis of patients, determining their prognosis, appropriate treatment selection, and clinical trial enrollment. Many testing panels are available, each with different abilities to detect various mutation types. Clinicians not only have to decide which test to use, but which specimen to test, and when and how often to test. Aside from unique mutations, immunotherapy markers have become important for the use of checkpoint inhibitors, and their detection and interpretation can also be challenging. Efforts are underway to simplify and validate these assays. Meanwhile, clinicians should become educated about the benefit of, means of, and interpretation of genomic testing patients across the disease course.

scholarly journals Advances and Limitations of Next Generation Sequencing in Animal Diet Analysis

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1854
Author(s):  
Gang Liu ◽  
Shumiao Zhang ◽  
Xinsheng Zhao ◽  
Chao Li ◽  
Minghao Gong
Keyword(s):  
Next Generation Sequencing ◽  
Environmental Changes ◽  
Diet Analysis ◽  
Next Generation ◽  
Application Range ◽  
Promising Tool ◽  
Composition And Structure ◽  
Next Generation Sequencing Ngs ◽  
Animal Diet ◽  
Generation Sequencing

Diet analysis is a critical content of animal ecology and the diet analysis methods have been constantly improving and updating. Contrary to traditional methods of high labor intensity and low resolution, the next generation sequencing (NGS) approach has been suggested as a promising tool for dietary studies, which greatly improves the efficiency and broadens the application range. Here we present a framework of adopting NGS and DNA metabarcoding into diet analysis, and discuss the application in aspects of prey taxa composition and structure, intra-specific and inter-specific trophic links, and the effects of animal feeding on environmental changes. Yet, the generation of NGS-based diet data and subsequent analyses and interpretations are still challenging with several factors, making it possible still not as widely used as might be expected. We suggest that NGS-based diet methods must be furthered, analytical pipelines should be developed. More application perspectives, including nutrient geometry, metagenomics and nutrigenomics, need to be incorporated to encourage more ecologists to infer novel insights on they work.

scholarly journals Differential Gene Expression in Patients With Prostate Cancer and in Patients With Parkinson Disease: an Example of Inverse Comorbidity

2021 ◽  
Author(s):  
Pietro Pepe ◽  
Simona Vetrano ◽  
Rossella Cannarella ◽  
Aldo E Calogero ◽  
Giovanna Marchese ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Causes Of Death ◽  
Genetic Factors ◽  
Target Genes ◽  
Lewy Bodies ◽  
Control Group ◽  
Healthy Donors ◽  
Differential Gene ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Prostate cancer (PCa) is one of the leading causes of death in Western countries. Environmental and genetic factors play a pivotal role in PCa etiology. Timely identification of the genetic causes is useful for an early diagnosis. Parkinson’s disease (PD) is the most frequent neurodegenerative movement disorder; it is associated with the presence of Lewy bodies (LBs) and genetic factors are involved in its pathogenesis. Several studies have indicated that the expression of target genes in patients with PD is inversely related to cancer development; this phenomenon has been named “inverse comorbidity”. The present study was undertaken to evaluate whether a genetic dysregulation occurs in opposite directions in patients with PD or PCa. In the present study, next-generation sequencing (NGS) transcriptome analysis was used to assess whether a genetic dysregulation in opposite directions occurs in patients with PD or PCa. The genes SLC30A1, ADO, SRGAP2C, and TBC1D12 resulted up-regulated in patients with PD compared to healthy donors as controls and down-regulated in patients with PCa compared with the same control group. These results support the hypothesis of the presence of inverse comorbidity between PD and PCa.

Recent Advances in Lynch Syndrome: Diagnosis, Treatment, and Cancer Prevention

2018 ◽  
pp. 101-109 ◽  
Author(s):  
Matthew B. Yurgelun ◽  
Heather Hampel
Keyword(s):  
Lynch Syndrome ◽  
Cancer Prevention ◽  
Checkpoint Inhibitors ◽  
Tremendous Progress ◽  
Cancer Prevention And Screening ◽  
Reduction Strategies ◽  
Neoplastic Process ◽  
Risk Reduction Strategies ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Identification of individuals with inherited predispositions to cancer, including Lynch syndrome, can help prevent cancer and cancer-related death by allowing for the uptake of specific cancer prevention and screening as well as the use of therapies directed toward the underlying neoplastic process for individuals with advanced cancer. In the 25 years since the discovery of microsatellite instability (MSI) and the first recognition of germline mismatch repair (MMR) gene variants as the etiologic basis of Lynch syndrome, there has been tremendous progress in the understanding of the spectrum of cancer risk associated with Lynch syndrome as well as in cancer prevention and risk-reduction strategies. The past few years, in particular, have brought transformative changes in the treatment of Lynch syndrome–associated cancers with immune checkpoint inhibitors. In parallel, advances in next-generation sequencing (NGS) technologies now allow rapid and scalable somatic and germline sequencing that promises to help identify Lynch syndrome in individuals who otherwise lack classic phenotypes. Last, real progress is being made to understand more sophisticated methods of precision cancer prevention, including chemotherapeutic prevention agents (e.g., aspirin) and strategies that leverage the immune system to facilitate primary cancer prevention in otherwise-healthy Lynch syndrome carriers.

scholarly journals Understanding the Significance of Mutations in Tumor Suppressor Genes Identified Using Next-Generation Sequencing: A Case Report

2016 ◽  
Vol 9 (2) ◽  
pp. 328-330
Author(s):  
Steven Sorscher
Keyword(s):  
Next Generation Sequencing ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Kinase Inhibitors ◽  
Next Generation ◽  
Suppressor Genes ◽  
Gene Therapies ◽  
Promising Tool ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Next-generation sequencing (NGS) of tumors has been heralded as a promising tool to identify ‘actionable’ abnormalities susceptible to therapies targeting these mutated genes. Inhibiting the oncoprotein expressed from a single dominant mutated gene (oncogene) forms the basis for the success of most of the targeted gene therapies approved in the last several years. The well over 20 FDA-approved kinase inhibitors for cancer treatment are examples [Janne et al.: Nat Rev Drug Discov 2009;8: 709–723]. These and other similar agents in development might prove effective therapies for tumors originating from tissues other than those for which these drugs are currently approved. Finding such mutations in tumors of patients through NGS is being aggressively pursued by patients and their oncologists. For identified mutated tumor suppressor genes (TSG) the challenge is really the opposite. Rather than inhibiting the action of an oncoprotein, targeting would involve restoring the activity of the wild-type (WT) TSG function [Knudson: Proc Natl Acad Sci USA 1971;249: 912–915]. Here, a case is reported that illustrates the implications of a mutated TSG (BRIP1) identified by NGS as potentially actionable. In such cases, measuring allelic mutation frequency potentially allows for the identification of tumors where the loss of heterozygosity of a TSG exists. Without substantial loss of expression of the WT TSG product, it would seem very unlikely that ‘replacing’ a WT TSG product that is not a lost product would be a useful therapy.

scholarly journals The Application of Next-Generation Sequencing to Define Factors Related to Oral Cancer and Discover Novel Biomarkers

Life ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 228
Author(s):  
Soyeon Kim ◽  
Joo Won Lee ◽  
Young-Seok Park
Keyword(s):  
Next Generation Sequencing ◽  
Oral Cancer ◽  
Genetic Alterations ◽  
Eligibility Criterion ◽  
Next Generation ◽  
Novel Biomarkers ◽  
Targeted Gene Therapy ◽  
Next Generation Sequencing Ngs ◽  
Potential Use ◽  
Generation Sequencing

Despite the introduction of next-generation sequencing in the realm of DNA sequencing technology, it is not often used in the investigation of oral squamous cell carcinoma (OSCC). Oral cancer is one of the most frequently occurring malignancies in some parts of the world and has a high mortality rate. Patients with this malignancy are likely to have a poor prognosis and may suffer from severe facial deformity or mastication problems even after successful treatment. Therefore, a thorough understanding of this malignancy is essential to prevent and treat it. This review sought to highlight the contributions of next-generation sequencing (NGS) in unveiling the genetic alterations and differential expressions of miRNAs involved in OSCC progression. By applying an appropriate eligibility criterion, we selected relevant studies for review. Frequently identified mutations in genes such as TP53, NOTCH1, and PIK3CA are discussed. The findings of existing miRNAs (e.g., miR-21) as well as novel discoveries pertaining to OSCC are also covered. Lastly, we briefly mention the latest findings in targeted gene therapy and the potential use of miRNAs as biomarkers. Our goal is to encourage researchers to further adopt NGS in their studies and give an overview of the latest findings of OSCC treatment.

Backtracking Subclonal Mutations Of TP53 In Myelodysplasia (MDS) With Del(5q) With Next-Generation Sequencing (NGS)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 520-520
Author(s):  
Laurence Lodé ◽  
Audrey Ménard ◽  
Marion Loirat ◽  
Maxime Halliez ◽  
Steven Richebourg ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Lower Limit ◽  
Clonal Evolution ◽  
Applied Science ◽  
Tp53 Mutations ◽  
Variant Detection ◽  
Serial Samples ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Landscape analyses of mutational patterns have shown that virtually all myelodysplastic syndromes (MDS) harbor somatic mutations in >80% of cases. These molecular alterations provide useful clonality markers with a potential for early diagnosis of MDS when only cytopenia without marked dysplasia is observed. These markers have been proposed as future prognostic tools to guide therapeutic strategies (Bejar et al., 2011; Itzykson et al, 2013; Mufti et al 2013). Mutational analysis is finally a good way to track disease complexity by deciphering oligoclonality in MDS and better understand clonal evolution. Alterations in the TP53 gene are the most common cause of tumor escape from apoptosis. The aim of this study was to identify TP53 mutations in consecutive samples of lower-risk MDS (IPSS ≤1) with del(5q)obtained at follow-up or progression after sequential classical treatments. Next-generation sequencing (NGS) was used to backtrack the mutant clone(s) identified in late samples. The study was performed both by conventional Sanger sequencing and NGS on a GS Junior Instrument (Roche Applied Science, Mannheim, Germany). For each sample, eight exons (4-11) were amplified from 320 ng of DNA with preconfigured primer plates provided within the IRON II study network. PCR reactions were performed using the FastStart High Fidelity PCR System kit (Roche Applied Science). After double purification with Agencourt AMPure XP beads (Beckman Coulter, Miami, FL), exon-specific amplicon pools were generated and quantified using the Quant-iT™ Broad-Range PicoGreen DNA Assay Kit (Invitrogen, Carlsbad, CA). Emulsion PCR was performed with GS Junior emPCR Reagents (Lib-A) (Roche Applied Science) using 5 x 106 beads at a copy per bead ratio of 0.6. Finally, a fraction of 5-7% enriched beads was loaded on GS Junior Titanium sequencing PicoTiterPlate kit (Roche Applied Science). Data were analyzed for sequence alignment and variant detection using the GS Junior Sequencer and GS Amplicon Variant Analyzer softwares, versions 2.7 and 2.9 (Roche Applied Science). The results were further processed using the Sequence Pilot software version 4.0.1 (JSI Medical Systems, Kippenheim, Germany). The sensitivity of variant detection was set to a lower limit of >1% for bidirectional reads. This threshold was chosen according to a recent study investigating the assay's lower limit of detection (Grossmann et al., 2013), thus underlining the strength of NGS to identify subclones at a low frequency, not detectable by conventional Sanger analysis. A total of 89 DNA samples were extracted from the cytogenetics pellets of a cohort of 40 MDS with del(5q). TP53 mutation analysis was performed on 40 initial and 49 follow-up or progression samples including serial samples for 23 subjects. The depth of coverage was at least 500X and up to 8,444X per amplicon. Of those samples obtained and analysed at time of last follow-up or progression, 14 (61%) had TP53 mutations, mostly in the DNA-binding domain. Performing backtracking on previously collected serial samples, TP53 mutations were retrieved by NGS in 43% of initial samples (n=6), which is different from what was previously described by Jädersten et al (2011). A complete scenario of clonal evolution was retrieved in 11 cases, evidenced by TP53 mutations and/or cytogenetics. These were always consecutive to treatment with lenalidomide, yet 6 of the 12 cases without clonal evolution were also consecutive lenalidomide. Figure 1 provides the example of a complete follow-up including nine time points. More correlation with treatment will be provided. Although lenalidomide remains the treatment of choice for MDS with del(5q), resistant subclones may survive and culminate even following therapy initiation. This theory was recently suggested by Landau et al. in CLL (2013) and our test results support this. Early detection of emerging subclones could lead to initiation of alternative treatment, and we thus propose that a monitoring of TP53 alleles is performed annually after the onset of therapy for MDS using NGS. Figure 1. Figure 1. Disclosures: Kohlmann: MLL Munich Leukemia Laboratory: Employment. Moreau:CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau.

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